Hepatic insulin clearance is closely related to metabolic syndrome components

Abstract

Objective: Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate the relationship between hepatic insulin clearance (HIC) and different components of metabolic syndrome and tested the hypothesis that HIC may predict the risk of metabolic syndrome.

Research design and methods: Individuals without diabetes from the Metabolic Syndrome Berlin Brandenburg (MeSyBePo) study (800 subjects with the baseline examination and 189 subjects from the MeSyBePo recall study) underwent an oral glucose tolerance test (OGTT) with assessment of insulin secretion (insulin secretion rate [ISR]) and insulin sensitivity. Two indices of HIC were calculated.

Results: Both HIC indices showed lower values in subjects with metabolic syndrome (P < 0.001) at baseline. HIC indices correlate inversely with waist circumference, diastolic blood pressure, fasting glucose, triglycerides, and OGTT-derived insulin secretion index. During a mean follow-up of 5.1 ± 0.9 years, 47 individuals developed metabolic syndrome and 33 subjects progressed to impaired glucose metabolism. Both indices of HIC showed a trend of an association with increased risk of metabolic syndrome (HICC-peptide odds ratio 1.13 [95% CI 0.97-1.31], P = 0.12, and HICISR 1.38 [0.88-2.17], P = 0.16) and impaired glucose metabolism (HICC-peptide 1.12 [0.92-1.36], P = 0.26, and HICISR 1.31 [0.74-2.33] P = 0.36), although point estimates reached no statistical significance.

Conclusions: HIC was associated with different components of metabolic syndrome and markers of insulin secretion and insulin sensitivity. Decreased HIC may represent a novel pathophysiological mechanism of the metabolic syndrome, which may be used additionally for early identification of high-risk subjects.

Figure 1

Relationship between HIC estimated as HIC_ISR (C and D) and HIC_C-peptide (A and B) and OGTT-derived indices of insulin secretion (1st-phase insulin secretion index [IS] [26]) in the entire cohort (n = 800; subjects with metabolic syndrome, n = 325; subjects without metabolic syndrome, n = 475). R² was calculated for linear and nonlinear restricted cubic spline regression models.

Figure 2

Risk of subsequent metabolic syndrome according to the respective median of ascending tertiles of two HIC indices. A: HIC calculated by C-peptide values. B: HIC calculated with use of ISR. Adjustment for age, sex, body weight, waist circumference, 1st-phase insulin secretion, and follow-up time. Error bars represent 95% CIs. The horizontal line at 1.0 represents the reference line. Participants were divided into tertiles, according to HIC values. Tertile cut points were determined from the combined group of case and control subjects.